6SAH
Crystal Structure of BRD4(1) bound to inhibitor BUX5 (11)
Summary for 6SAH
| Entry DOI | 10.2210/pdb6sah/pdb |
| Descriptor | Bromodomain-containing protein 4, ~{N}-(2-methoxy-5-piperidin-1-ylsulfonyl-phenyl)-3-methyl-4-oxidanylidene-5,6,7,8-tetrahydro-2~{H}-cyclohepta[c]pyrrole-1-carboxamide (3 entities in total) |
| Functional Keywords | brd4, brd4(1), inhibitor, bromodomain, epigenetic reader protein, acetylated, lysine, histone tail, protein binding-inhibitor complex, bux5, fragment, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 15558.94 |
| Authors | Huegle, M. (deposition date: 2019-07-16, release date: 2020-12-09, Last modification date: 2024-01-24) |
| Primary citation | Hugle, M.,Regenass, P.,Warstat, R.,Hau, M.,Schmidtkunz, K.,Lucas, X.,Wohlwend, D.,Einsle, O.,Jung, M.,Breit, B.,Gunther, S. 4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines. J.Med.Chem., 63:15603-15620, 2020 Cited by PubMed Abstract: Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven. PubMed: 33275431DOI: 10.1021/acs.jmedchem.0c00478 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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